The diagnosis of Type 1 diabetes (T1D) is currently limited by methods that detect the disease at relatively late stages, when blood glucose levels rise and autoimmune attack is well underway. By this stage, given the treatments presently available (insulin injection), the b cell loss is de facto, irreversible. Biomarkers for early detetion of ? cell stress, before this late stage, would improve diagnosis and open up new windows to monitor and possibly treat the disease. We will produce functionally mature, never-before-stressed, ? cells from human pluripotent stem cells and use these cells to identify biomarkers for the earliest stages of ? cell stress by providing various stress conditions ex vivo. In additin, we can use stem cells from T1D and control patients to investigate differences in their ? ell responses to stress. In other words, we can ask: are ? cells in T1D patients especially sensitive to stress or in other ways defective before an immune attack? Successful identification of early ? ell-specific biomarkers for stress will enable earlier detection and diagnosis, better tracking f progress from asymptomatic to clinical presentation, and a more mechanistic understanding of the earliest stages and possibly initiating events of human T1D.